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Method for preparing clioquinol and diiodohydroxyquinoline by one-pot method

A technology for clioquinol and diiodoquinoline is applied in the field of preparing clioquinol and diiodoquine in one pot, and can solve the problems of poor atom economy, harsh reaction conditions, increasing the difficulty of purification, and the like. High productivity and environmentally friendly results

Pending Publication Date: 2021-08-24
CHANGZHOU VOCATIONAL INST OF ENG
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Problems solved by technology

[0004] The object of the present invention is to, overcome the defective that exists in the prior art, provide a kind of method for preparing clioquinol and biiodoquinoline by one-pot method, effectively solve following problem: (1) solve the non-directing group, When first C5 halogenation and then C7 iodination, because the hydroxyl group is the ortho-para positioning group, the problem of the high ratio of isomers in the reaction product also increases the difficulty of purification; (2) solves the problem of no directing group, first When C7 iodide is replaced by C5 halogenation, the yield of C7 iodide reaction in the first step is low (66%). Although the C5 halogenated product can be obtained in the follow-up, the total yield is only about 60%, that is, this The inventive method effectively overcomes the deficiencies such as poor atom economy, harsh reaction conditions, and cumbersome post-treatment steps that are common in the above two methods, and provides an efficient synthetic method for the preparation of clioquinol and diiodoquinoline. It has the characteristics of green environmental protection, atomic economy, simple operation and easy enlargement.

Method used

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  • Method for preparing clioquinol and diiodohydroxyquinoline by one-pot method

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Experimental program
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Effect test

Embodiment 1

[0025] Adopt the inventive method to prepare 5-chloro-7-iodoquinolin-8-alcohol (Ia), i.e. clioquinol, the reaction formula is as follows:

[0026]

[0027] S1: Put 8-hydroxyquinoline (compound II) (7.25g, 50mmol), acetic anhydride (60mL) and glacial acetic acid (20mL) into a 150mL reaction flask, reflux for 5h, and the reaction solution was concentrated to dryness under reduced pressure to obtain White powdery solid quinolin-8-yl acetate (compound III), directly carried out the next step reaction without purification;

[0028] S2: Add the quinolin-8-yl acetate (compound III), dichlorohydantoin (6.90 g, 35 mmol), benzyltriethylammonium chloride (TEBA) ( 2.28g, 10mmol) and water 75mL, stirred and reacted at 50°C for 12h, filtered the reaction liquid, washed with a small amount of ice water to obtain off-white powdery solid 5-chloroquinolin-8-yl acetate (Compound IVa), the wet product was not purified proceed directly to the next reaction;

[0029] S3: 5-chloroquinolin-8-yl ...

Embodiment 2

[0035] Adopt the inventive method to prepare 5,7-diiodoquinolin-8-alcohol (Ib), i.e. diiodoquinoline, reaction formula is as follows:

[0036]

[0037] S1: Put 8-hydroxyquinoline (compound II) (7.25g, 50mmol), acetic anhydride (60mL) and glacial acetic acid (20mL) into a 150mL reaction flask, reflux for 5h, and the reaction solution was concentrated to dryness under reduced pressure to obtain White powdery solid quinolin-8-yl acetate (compound III), directly carried out the next step reaction without purification;

[0038] S2: Put quinolin-8-yl acetate (compound III), diiodohydantoin (13.30g, 35mmol), TEBA (2.28g, 10mmol) and water 75mL prepared in step S2 into a 150mL reaction flask, 50 Stir the reaction at ℃ for 12 hours, filter the reaction solution, wash with a small amount of ice water to obtain off-white powdery solid 5-chloroquinolin-8-yl acetate (compound IVb), and the wet product is directly carried out to the next step reaction without purification.

[0039] S3: ...

Embodiment 3

[0045] Adopt the inventive method to prepare 5-chloro-7-iodoquinolin-8-alcohol (Ia), i.e. clioquinol, comprises the steps:

[0046] S1: Put 8-hydroxyquinoline (compound II) (7.25g, 50mmol), acetic anhydride (60mL) and glacial acetic acid (20mL) into a 150mL reaction flask, reflux for 5h, and the reaction solution was concentrated to dryness under reduced pressure to obtain White powdery solid quinolin-8-yl acetate (compound III), directly carried out the next step reaction without purification;

[0047] S2: Put quinolin-8-yl acetate (compound III), dichlorohydantoin (6.90g, 35mmol), TEBA (2.28g, 10mmol) and water 75mL prepared in step S1 into a 150mL reaction bottle, 100 Stir the reaction at ℃ for 12 h, filter the reaction solution, and wash with a small amount of ice water to obtain 5-chloroquinolin-8-yl acetate (compound IVa) as a yellow powder solid, and the wet product is directly carried out to the next step reaction without purification.

[0048] S3: 5-chloroquinolin-8-...

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Abstract

The invention discloses a method for preparing clioquinol and diiodohydroxyquinoline by a one-pot method, and effectively solves the following problems: (1) the problem that the proportion of isomers in a reaction product is too high due to the fact that hydroxyl is an ortho- / para-positioning group and the purification difficulty is increased when no guiding group exists and C5 halogenation is performed firstly and then C7 iodination is performed is solved; and (2) the problem of low yield (66%) of the first-step C7-site iodination reaction when no guiding group exists and C7 iodination is performed firstly and then C5 halogenation is performed is solved, and the total yield is only about 60% although a C5-site halogenation product can be obtained subsequently. The method effectively overcomes the ubiquitous defects of poor atom economy, harsh reaction conditions, tedious post-treatment steps and the like in the two methods, and is suitable for industrial production. The invention provides an efficient synthesis method for preparing the clioquinol and diiodohydroxyquinoline, and the method has the characteristics of greenness, environmental protection, atom economy, simplicity in operation, easiness in amplification and the like.

Description

technical field [0001] The invention relates to the technical field of organic synthesis, in particular to a method for preparing clioquinol and diiodoquinoline in one pot. Background technique [0002] 5-Chloro-7-iodo-8-hydroxyquinoline and 5,7-diiodo-8-hydroxyquinoline, usually called clioquinol and diiodoquinoline respectively, are mainly used clinically Treat malaria. Since 2005, studies have reported that clioquinol has the effect of inducing tumor cell apoptosis, and subsequent studies on the anti-tumor mechanism of clioquinol have shown that clioquinol induces apoptosis of cancer cells through a variety of cellular pathways. The anti-tumor research of clioquinol has been further deepened; diiodoquinoline, as an analog of clioquinol, is mainly used for the treatment of amebiasis, both of which have important medicinal value. [0003] Multiple literatures (iScience, 2020, 23(5): 101072; Chem.Sci., 2018, 9, 1782; RSCAdvances, 2015, 5, 88311; J.Org.Chem., 2005, 70, 8590...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/28
CPCC07D215/28
Inventor 江雨佳贺新陈蕾高长娜王铭扬周海平
Owner CHANGZHOU VOCATIONAL INST OF ENG
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